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​With Jessica Scott, PhD, of Memorial Sloan Kettering Cancer Center

By Sarah DiGiulio

Exercise is one of the top health-promoting behaviors an individual can adopt. It's known to lessen risk of heart problems, cognitive decline, some cancers, and mental health disorders, as well as all-cause mortality (death by any cause). And new research suggests those benefits are also true for survivors of childhood cancer survivors.

"Childhood cancer survivors remain at substantially elevated risk of mortality with life expectancy shortened, on average, by 10 years compared with the general population," noted Jessica Scott, PhD, Assistant Member in the Department of Medicine at Memorial Sloan Kettering Cancer Center, New York City, and a coauthor of the new research. "This is primarily due to treatment-related effects (such as, subsequent malignant neoplasms and cardiovascular disease, [among others]). Given this excess risk, we know that strategies that can offset treatment-related effects are of major clinical importance."

The study, published online ahead of print in JAMA Oncology, was a multicenter cohort analysis of 15,450 adults who had been diagnosed with cancer before age 21 from pediatric hospitals in the U.S. and Canada between 1970 and 1999 (2018; doi:10.1001/jamaoncol.2018.2254). The individuals were all part of the Childhood Cancer Survivor Study and were followed through 2013. The researchers looked at the association between weekly self-reported vigorous exercise and mortality (including overall death rates and cause-specific death rates).

The data showed in a median analysis after 10 years and in the full analysis after 15 years that the cumulative incidence of all-cause mortality was in fact higher for those with lower weekly vigorous exercise and lower for those who did more vigorous exercise on a weekly basis.

After 15 years, there was a significant inverse association between exercise and all-cause mortality such that, compared to those reporting no weekly vigorous exercise, those reporting approximately 1.5-2 hours per week of vigorous exercise had a 42 percent reduction in mortality, Scott said.

Another analysis of the data showed that after an 8-year period, those who increased weekly exercise by as little as 40 minutes per week saw a 40 percent reduction in all-cause mortality, compared to those who kept their exercise at about 30 minutes or less per week over that time.

The amount of exercise that conferred the most benefit to survivors of childhood cancer (in terms of reducing risk of all-cause mortality) was equivalent to about 1.5-2 hours of brisk walking per week. "However, benefits were observed even with approximately 40 minutes per week of vigorous exercise," Scott said, noting this data was observational, so randomized controlled trials would be needed to more accurately identify an ideal dose. Here's why Scott says this new data is so important.

1. What does this data tell us that we didn't already know about the late effects of childhood cancers and survivors' risks?

"In the general population, adherence to healthy lifestyle behaviors, including regular exercise, is associated with substantial reductions in cardiovascular disease mortality and mortality from any cause. Exercise also reduces the primary incidence of several forms of cancer and the risk of recurrence following a diagnosis of certain adult-onset cancers (like those of the breast, colon, and prostate).

"But whether these findings extended to adult survivors of childhood cancer with excess risk of mortality was not known. Accordingly, we wanted to evaluate the association between exercise in early adulthood and change in vigorous exercise on mortality in long-term adult survivors of childhood cancer participating in the Childhood Cancer Survivorship Study.

"This study was unique in that it included a large sample size (of more than 15,000 cancer survivors); it included a long-term duration of follow-up [including a median follow-up at approximately 10 years]; it focused on at least 5-year survivors of cancer; and [it investigated] change in exercise exposure (median interval of approximately 8 years)."

2. What types of interventions are needed to spread this message that survivors of childhood cancers need to be exercising?

"One common question by patients is 'what is the best exercise program for me?' This is one of the most important questions in exercise-oncology research and one that will likely require many years to answer. What we've found is that one size of exercise does not fit all. However, based on current evidence in oncology settings, as a first step, patients may need to check with a doctor before beginning an exercise program.

"Once cleared for activity, the exercise guidelines for cancer patients/survivors are to: 1) avoid inactivity; 2) if relatively new to exercise, perform either 150 minutes of moderate-intensity aerobic physical activity or 75 minutes of vigorous-intensity aerobic physical activity each week; and 3) if a regular exerciser, try increasing the moderate-intensity physical activity to 300 minutes or your vigorous-intensity physical activity to 150 minutes each week.

"These recommendations can be achieved by adding a few minutes of activity to a daily routine, such as taking the stairs, adding an extra 15-minute walk before/after work (or at lunch), or walking a little faster or changing a walking route from a flatter route to one with a few small hills. There are also cancer-experienced exercise specialists (clinical exercise physiologists, kinesiologists, and physiotherapists) and programs (such as LIVESTRONG at the YMCA) that can help to initiate a new exercise program following a cancer diagnosis. Small steps can make a big difference for cardiovascular health."

3. What is the takeaway message about this new work?

"There are currently approximately 16 million adult cancer survivors in the U.S., of which approximately 500,000 are adult survivors of childhood malignancies. These numbers are estimated to reach approximately 24 million [cancer survivors] and approximately 750,000 [adult survivors of childhood cancers], respectively, by the year 2030.

"Our findings support counseling all survivors, whenever appropriate, to increase participation in vigorous exercise for approximately 60 minutes a few days a week."

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Posted by Sarah DiGiulio at 4:40 PM

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​With Belle H. de Rooij, MSc, of the Center of Research on Psychology in Somatic Diseases at Tilburg University

By Sarah DiGiulio

Does an optimistic versus pessimistic outlook when it comes to a cancer prognosis (on the part of the patient) bear on the outcome for that patient? Some research has suggested illness perceptions are linked to quality-of-life outcomes and may even be linked to higher survival, too.

Now a new study adds more evidence that patients' perceptions about their cancer can provide important information to health care providers about future outcomes, better accounting for disease severity than other previous research, according to lead author Belle H. de Rooij, MSc, a PhD candidate at the Center of Research on Psychology in Somatic Diseases in the Department of Medical and Clinical Psychology at Tilburg University in the Netherlands (Cancer 2018; doi.org/10.1002/cncr.31634).

"In an era of increased interest in care for cancer survivors and counselling, it is important to consider the benefits of realistic illness perceptions among cancer survivors compared to optimistic or pessimistic illness perceptions with regard to prognosis," de Rooij shared with Oncology Times.

Researchers used survey data from the population-based Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship registry, along with clinical and survival data from the Netherlands Cancer Registry. The researchers analyzed data for 2,457 patients diagnosed with cancer (either colon, rectal, prostate, endometrial, or ovarian cancers, or non-Hodgkin lymphoma) at least 5 years prior.

A series of questions within the survey asked about illness perceptions. The researchers used the results from those questions to categorize patients as either having a realistic illness perception (one consistent with prognosis), an optimistic illness perception (a less threatening view than their prognosis would suggest), or a pessimistic illness perception (a more threatening view than their prognosis would suggest).

The data showed that an optimistic illness perception was linked not only to better health-related quality of life, but also to better survival.

1, What was new about the results from this data?

"Cancer survivors who have optimistic illness perceptions with respect to their prognosis at the time of the questionnaire appear to have the most favorable health-related quality of life and survival compared to survivors with either realistic or pessimistic illness perceptions. Cancer survivors who have pessimistic illness perceptions with respect to their prognosis at the time of the questionnaire appear to have the worst health-related quality of life and survival.

"Previous evidence suggests that interventions providing explicit information about the diagnosis, side effects, and prognosis of the cancer may increase illness perceptions, resulting in illness perceptions that are possibly more concordant with the disease severity or prognosis. However, it remained unclear whether these more 'realistic' perceptions about the disease were either harmful or beneficial for survivors.

"To our knowledge, this is the first study that explores illness perceptions relative to disease severity (prognosis). Previous studies demonstrated that higher (more threatening) illness perceptions are associated with worse health-related quality of life, psychological morbidities, and worse survival. However, given the findings that patients with more severe disease generally have higher (more threatening) illness perceptions, the relationship between illness perceptions and outcomes may largely be explained by disease severity. This study provides evidence on the benefits of perceptions that are realistic with respect to prognosis compared to more optimistic or pessimistic illness perceptions."

2. What are the implications of this research in terms of informing practice?

"Our findings do indeed suggest that optimistic perceptions may be more beneficial. However, it could also be true that the optimistic and pessimistic individuals were realistic, too, because their illness perceptions may be a much more inclusive reflection of their state of health than our set of objective measures regarding prognosis comprises.

"Therefore, we think it is most important that care providers acknowledge pessimistic illness perceptions among cancer survivors and try to understand why these individuals have pessimistic illness perceptions, because these they may require additional support. For patients, it might be important to find additional help when perceptions are more pessimistic than would be expected based on prognosis."

3. So what's the most important takeaway?

"Survivors with illness perceptions that are relatively optimistic with respect to their prognosis appear to have the most favorable outcomes, whereas those with pessimistic illness perceptions relative to their prognosis have the worst outcomes compared to those with realistic illness perceptions. While illness perceptions may be important predictors of health outcomes independent of prognosis, we think it is important to understand why individuals may hold pessimistic illness perceptions, and provide support that is appropriate for this group to improve their outcomes.

"It is important that care providers are aware of the potential harmful effects of diagnostic and prognostic information provision as they may increase illness perceptions, and that they should carefully monitor the perceptions of patients when providing such information.

"Perhaps there is no one-size-fits-all approach to counseling for cancer survivors, but we may need individualized approaches to prevent potential harmful effects on illness perceptions and related outcomes. Further research in this field is warranted."

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Posted by Sarah DiGiulio at 4:26 PM

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​With Anna Dorothea Wagner, MD, of the Lausanne University Hospital in Switzerland

By Sarah DiGiulio

Precision medicine is a hot topic in oncology right now. Check any oncology meeting schedule and you'll likely find at least one session on the topic. It makes sense. It's the idea that treating different patients with the same therapeutic approach may not result in the same outcome—given their genetics, their previous health status, their psychosocial needs, and numerous other factors.

And one of those factors that deserves a lot more attention is gender, according to Anna Dorothea Wagner, MD, an oncologist at the Lausanne University Hospital in Switzerland. She recently co-authored a comment within the "Comments and Controversies" section of the Journal of Clinical Oncology to bring more awareness to the issue of identifying sex differences in clinical trials (2018;36:2680-2683).

"Sex may have an impact on the efficacy and toxicity of all kinds of drugs," she told Oncology Times. "We need to learn more about it."

For some drugs (like 5-fluorouracil [5-FU], for example), evidence clearly shows there's more toxicity when used in women compared with men, she noted. But for other drugs, it's unknown (JAMA Oncol 2018;4:1003-1006). "And we need to learn more about it."

Other data show that women are at higher risk of things like mucositis, nausea and emesis, and alopecia when they take certain cancer drugs for several types of cancer, Wagner and her coauthors noted in the study. For other drugs, there's evidence sex differences may change how well the drugs work in treating some cancers. And there's more evidence still that gender may affect tumor biology, which could mean that developing sex-specific strategies for treatment (in terms of dose and types of drug) might improve outcomes.

Wagner told Oncology Times why the issue warrants attention and what she suspects effective next steps will be.

1. Why did you decide to write this editorial with your coauthors and why now?

"I work as a gastrointestinal oncologist and see many patients. I had several women, especially women with pancreatic cancer who had been treated with FOLFIRINOX (but after other treatments, too), who had major side effects—not only nausea and vomiting, but fatigue, diarrhea, and hematological toxicities, too.

"It was those clinical observations, and the suspicion of greater toxicities in women. I wondered why this was the case. These were patients in their 50s, motivated and dynamic, and in many cases managing full-time jobs [and/or] kids, who became too weak to leave [their couches] for at least 1 week after the treatment, and even in the second week they were too tired to do anything.

"They had no other reasons to develop such major side effects. So I suspected finally that it might be their sex. I looked in the literature and found some—but overall little—data on sex differences in side effects from chemotherapy.

"We then did a [secondary] analysis of the PETACC-3 trial, which confirmed the observation of significant higher toxicities in women for both 5-FU and FOLFIRI (JAMA Oncol 2018;4:1003-1006). The more I learned about the topic, the more interesting it became."

2. In your opinion, what are some of the reasons that sex differences have not been well-investigated in cancer research, particularly in terms of treatment and treatment efficacy?

"The discipline which systematically analyzes sex differences is gender medicine. For example, in Berlin and Vienna, medical faculties have a chair for Gender Medicine. At Stanford University, there is the Gendered Innovations in Science, Health & Medicine, Engineering, and Environment (to 'harness the creative power of sex and gender analysis for innovation and discovery,' according to the department's website).

"I think oncology could benefit significantly from this approach.

"The pioneer in gender medicine, Marianne Legato, MD, PhD, was a cardiologist. Following her initiative, much has been learned in the field of cardiology. In oncology, this work needs to be done. We just have not yet had the pioneers in this field."

3. The FDA and NIH have made some efforts in defining guidelines for participation in clinical trials. Why have previous steps not been significant enough to push the needle when it comes to this issue?

"They have certainly made important steps, but more remains to be done. The founding of the U.S. Department of Health and Human Services Office on Women's Health is an important step.

"However, the focus on women's health is not enough. I am not sure if that office will consider the question: for a drug with higher efficacy and a higher, but still acceptable toxicity in women, the dose in men might need to be increased to achieve a similar level of efficacy.

"The point is that what is the optimal treatment for a man might not necessarily be the optimal treatment for a woman. Current medical research needs to take this into account.

"Large databases which analyze systematically the effect of a patient's sex on all types of outcomes—efficacy and toxicity—are needed. If such differences are detected, they need to be correlated with pharmacokinetic data. As a function of the results, dose modifications according to sex may need consideration."

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Posted by Sarah DiGiulio at 1:02 PM

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The numbers of advanced practice providers involved in oncology is quickly growing. The number of U.S. oncology practices who've reported employing advanced practice providers has jumped from 52 percent in 2014 to 81 percent in 2017, according to ASCO's annual Practice Census Survey (J Oncol Pract 2018;14:e412-e420).

To better understand the role and scope that these advanced practice providers—including nurse practitioners and physician assistants—play in cancer care, several major health groups collaboratively conducted and published a survey to identify such providers. The data was published in the Journal of Oncology Practice (2018;14:e518-e532).

"There has been a great deal of interest in the role of advanced practice providers in oncology, but a limited understanding of how many advanced practice providers practice in this area, what services they provide, what influences their practice, and how they are compensated," survey co-author Todd Pickard, MMSc, PA-C, DFAAPA, Director of Physician Assistant Practice at The University of Texas MD Anderson Cancer Center and Chair of ASCO's Workforce Advisory Group that worked on the survey, shared with Oncology Times.

The collaboration included ASCO, the American Academy of Physician Assistants (AAPA), the Association of Physician Assistants in Oncology (APAO), the Advanced Practitioner Society for Hematology and Oncology (APSHO), and the Oncology Nursing Society.

"There has been a well-published disconnect between demand for oncology services and the supply of providers available to meet this growing demand," Pickard said. "One of the solutions to close this gap between supply and demand is the addition of advanced practice providers as oncology providers and integration into the care team.

"Oncology practices have real-world needs to respond to their communities and advanced practice providers have been a valuable resource to meet these needs. It simply makes sense that this growth has occurred and will likely continue," he added.

The analysis identified 5,350 advanced practice providers currently working in oncology, though the paper notes there could be as many as 7,000. The data also includes information about the demographics of those providers, as well as the roles they play and challenges they face.

According to the paper, it is the first detailed examination of advanced practice providers in oncology. Pickard further explained what the new data revealed.

1. What findings stood out to you?

"Several items stand out: 1) It is still very difficult to get a true 'census' of advanced practice providers in oncology due to limitations in how they are accounted for in the health care system. Many times their contributions are hidden in co-managed work and billing data that is attributed to our physician colleagues.

"2) Advanced practice provider practice in oncology is heavily influenced by physician preferences rather than patient care demands or standardization of the advanced practice provider role.

"3) Advanced practice providers in oncology have unique educational needs to ensure that they are fully prepared to provide the complex care of the oncology patient. ASCO, APSHO, APAO, and AAPA have worked to create in-person meetings, web-based learning, and other medical knowledge tools to meet these needs.

"4) There has been a very rapid growth and wide acceptance of the advanced practice provider in oncology since 2014."

2. How is the increasing presence of advanced practice providers in oncology care changing how care is delivered?

"The growing presence of advanced practice providers in oncology has created several opportunities for increasing patient access to care, quality of care, coordination of care, new services for cancer survivors, and safer care. When you have a fully integrated care team of physicians, advanced practice providers, nurses, pharmacists, social workers, and business/office staff, the team is positioned and resourced to provide the entire spectrum of care for oncology patients.

"This care is incredibly complex and relies on the knowledge, skills, and engagement of the entire team. Advanced practice providers fit perfectly into the area of need.

3. What are the implications of these findings and what's most important for practicing oncologists and all cancer care providers to know about this research?

"This is great news for oncology physicians. They have the opportunity to work with advanced practice providers who can become critically important and valuable members of the team that improve the care for patients with cancer. Advanced practice providers have a proven track record in oncology and this enables physicians to understand and embrace [their] role in oncology.

"Advanced practice providers have a critical role in the delivery of oncology care that brings value, quality, and safety to those we serve. Advanced practice providers are focused on team-based care that is perfectly suited to the complex care of the patient with cancer."

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Posted by Sarah DiGiulio at 2:59 PM

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​With Emily Largent, PhD, JD, RN, at the Perelman School of Medicine at University of Pennsylvania

By Sarah DiGiulio

In a recent JAMA Oncology Viewpoint article, two medical ethics experts from the University of Pennsylvania argue it's time to revise how we reimburse and incentivize cancer clinical trial participation (2018;4:913-914).

The authors—Emily Largent, PhD, JD, RN, Assistant Professor, and Holly Fernandez Lynch, JD, MBe, Assistant Professor and Assistant Faculty Director of Online Education, both in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine at University of Pennsylvania—say reimbursement for clinical trial-related expenses will help make access to investigational drugs and treatments more equitable. In particular, access will be fairer for people of lower socioeconomic status (as trial participants often incur out-of-pocket expenses for supportive care that is not covered by the trial sponsor). Such expenses may be for travel and lodging for the purpose of participating in the trial, as well as copayments, co-insurance, and deductible payments associated with usual care received over the course of a trial.

FDA policy does not discourage reimbursement to patients for clinical trial-related expenses, and a recent policy update explicitly states it's not coercive or unduly influential to do so. Largent and Lynch suggest, however, that this stand is too narrow—and there are other permissible uses for payment including compensation for time and effort, as well as incentives to encourage patients to participate in clinical trials.

Some states have considered passing state-level laws that clarify that reimbursement of clinical trial-related expenses (such as travel and lodging) is not coercive, which, according to Largent and Lynch, is appropriate.

Oncologists and cancer care providers can (and should) be advocates for addressing these barriers to clinical trial participation, Largent explained. "People need to be aware that clinical trials are not 'free'—but the research is incredibly important."

Here's what else Largent told Oncology Times about the issue.

1. What prompted you to write this editorial and why is the issue so important now?

"This issue came to my attention because I live in a state (Pennsylvania) that is currently considering such an act [that would clarify that reimbursement for clinical trial-related expenses is not coercive]. I have been working on issues related to paying research participants for years—and most attention is focused on issues of payment at the federal level. So, this felt like a novel approach.

"A lot of cancer trials fail to enroll the target number of participants. In extreme cases, the trial may have to close prematurely; in other cases, there may be less statistical power to answer the questions of interest. If we could address financial barriers to trials, we might be able to recruit more people into trials.

"In addition, a common concern is that we want to distribute the burdens and benefits of clinical trial participation evenly over the population—and addressing financial barriers may help ensure that this distribution of burdens and benefits is more even."

2. What are the costs of participating in a clinical trial?

"There isn't typically an 'entry fee' to be enrolled in a clinical trial. And, in many cases, the investigational drug or experimental intervention will be paid for by a sponsor; and usual care will be covered by the insurer.

"However, individuals may still have to pay for travel and lodging or assume increased copayments and deductibles (on the usual care). These expenses may not be immediately obvious to trial participants but can be significant.

"People often talk about the 'financial toxicity' of cancer therapy—that is, treatment-related financial hardship. But there is increasing evidence that participating in cancer clinical trials can have additional financial toxicity, and that is not something that is discussed enough. Participating in clinical trials can require patients to assume out-of-pocket costs, such as travel and lodging for study visits or increased copayments and deductibles. This expense can be a barrier to trial participation for a lot of people."

3. Your editorial explains several options to incentivize clinical trial participation by offering payment from expense reimbursement to compensation. What do you think is the best option?

"I think that the default should be reimbursing people for out-of-pocket expenses and offering compensation for their time and effort. Although I think this is possible within existing regulations, institutional review boards may be hesitant to do this out of fear that offering payment will distort the patient's decision about whether or not to participate in research. So, it would help for the Office of Human Research Protections and the FDA to further clarify that offering payment is acceptable and even desirable. This might calm some anxiety around payment, which is an important first step."

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Posted by Sarah DiGiulio at 6:53 PM

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Do You Have a Question?

Sarah DiGiulio

The “3 Questions on…” blog asks oncology’s thought leaders for their perspectives and takes on the field’s current news and controversies. Want to get answers to your questions? Add a comment or email Pam Tarapchak at pam.tarapchak@wolterskluwer.com or Catlin Nalley at catlin.nalley@wolterskluwer.com to suggest a topic for a future column. We want to hear from you!